The role(s) of central Gα-proteins in the regulation of cardiovascular and renal function is unknown. We examined how inhibition/downregulation of central Gαi/Gαo, Gαz or Gαq proteins altered the characteristic cardiovascular (depressor), renal excretory (diuretic), and plasma AVP (inhibitory) responses to intracerebroventricular injection of nociceptin/orphanin FQ (N/OFQ) in rats. Before investigation, rats were pretreated intracerebroventricularly with saline vehicle (5 μl, 48 h, n = 6), pertussis toxin (PTX; 48-h, 1 μg, n = 6), or Gαz, Gαq, or scrambled oligodeoxynucleotide (ODN) (25 μg, 24 h, n = 6 per group). On the study day, intracerebroventricular N/OFQ (5.5 nmol) or vehicle (5 μl) was injected into pretreated conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were recorded, and urine was collected for 90 min. In vehicle or scrambled ODN groups, intracerebroventricular N/OFQ decreased MAP and HR and produced water diuresis (sensitive to UFP-101, N/OFQ receptor antagonist). The hypotension and bradycardia, but not diuresis, to N/OFQ were abolished in PTX-pretreated rats. In contrast, intracerebroventricular ODN pretreatment markedly blunted (Gαz) or augmented (Gαq) the diuresis to intracerebroventricular N/OFQ. In separate studies, the action of central N/OFQ to decrease plasma AVP levels in naïve water-restricted rats was differentially altered by intracerebroventricular Gαz ODN (blunted) and Gαq ODN (augmented) pretreatment. These studies demonstrate central Gαi/Gαo activity mediates intracerebroventricular N/OFQ's cardiovascular depressor function. Alternatively, central Gαz (inhibitory) and Gαq (stimulatory) activity differentially modulates AVP release to control the pattern of diuresis to intracerebroventricular N/OFQ. These findings highlight the novel selective central Gα-subunit protein-mediated control of cardiovascular vs. renal excretory function.